This invention relates to the use of purified SDG (secoisolariciresinol diglucoside) as a hypotensive (vasodilator) agent in treating hypertension or reducing or preventing the development of elevated blood pressure.
Hypertension is one of the leading causes of deaths in this society. According to a survey done between 1986-1992, the overall prevalence of hypertension in the Canadian population was 22% and was higher in men (26%) than in women (18%). There is overwhelming evidence that elevated systolic or diastolic blood pressure or both, increases the probability of ischemic heart disease, stroke, atherosclerosis and overall mortality. The causes of death in hypertensive are heart failure (45%), heart attack (35%), stroke (15%) and kidney failure (5%). Treatment and control of high blood pressure reduce the risk of ischemic heart disease and stroke. Ischemic heart disease is the leading cause of death and hospitalization.
The present treatments of hypertension and ischemic heart disease have side effects and are expensive. The drugs used for treating hypertension include diuretics, antiadrenergic agents, vasodilator, central agonists, angiotensin converting enzyme inhibitors, calcium channel blockers, and angiotensin II receptor antagonists.
Diuretics reduce blood potassium, increase serum cholesterol, LDL-cholesterol and triglycerides, are diabetogenic, and produce gout. Beta-adrenergic blockers produce insomnia, fatigue, sexual dysfunction and exacerbation of asthma, increases serum cholesterol and triglycerides, and produce cold hands. Angiotensin converting enzyme inhibitors could cause cough, angioedema, urticaria and loss of white blood and other blood cells. Calcium channel blockers produce flushing, headaches, palpitation and swelling of ankles.
For treatment of ischemic heart disease (angina pectoris, myocardial infarction) the physiologic basis of treatment with drugs are to reduce oxygen demand and increase oxygen supply. For this purpose, the vasodilator (nitrites and nitrates), beta-adrenergic blocker, calcium channel blockers are generally being used.
Nitrites and nitrates produce headache, flushing face, and reflex tachycardia. Reflex tachycardia would increase the oxygen consumption of the heart and hence would counteract to some extent the beneficial effect of nitrites and nitrates in ischemic heart disease. Also nitrites and nitrates produce tolerance.
The drugs used for the treatment of hypertension and ischemic heart disease are also very expensive. Side effects common to drugs, especially antihypertensive drugs, together with high cost of the drugs, have always been a major cause of noncompliance and concern. It is particularly difficult to accept treatment-related symptoms for a life-long disease, especially hypertension. For example, a research conducted by J. Menard [Improving hypertension treatment. Where should we put our efforts: new drugs, new concepts, or new management? (1992) Am. J. Hypertens. 5(12 Pt 2): 252S-258S] revealed that current treatment failure is frequent and side effects are common. The results showed that in the systolic hypertension in the elderly program, 28 to 35% of patients did not reach the goal blood pressure, 13% stopped treatment because of side effects, and 21% required medication other than a diuretic and a beta-blocker.
Therefore, despite the availability of numerous antihypertensive agents, a concerted research effort to develop new approaches to hypertension treatment is necessary.
Prasad, U.S. Pat. No. 5,846,944 describes the use of purified SDG for the treatment of hypercholesterolemic atherosclerosis and for reducing total cholesterol, as well as for the treatment of diabetes mellitus. Atherosclerosis is lipid deposit in the arteries and hence narrowing of blood vessels, resulting in ischemic heart disease.
The literature also describes the beneficial effect of flaxseed to reduce ascites and pulmonary hypertension in broiler chickens [J. Bond et al. (1996) Effect of dietary flax oil and hypobaric hypoxia on right ventricular hypertrophy and ascites in broiler chickens. British Poultry Science 37(4): 731-741]. Researchers have also inferred a role for flax in diet of patients with ischemic heart disease, hyperlipidemia and high blood pressure. [I. A. Rozanova et al. (1997) Effect of antiatherosclerotic diet, containing polyunsaturated fatty acids of the omega-3 family from flax oil, on fatty acid composition of cell membranes of patients with ischemic heart disease. Vopr. Pitan. (5): 15-17]. It has been shown that alpha-linolenic acid has a beneficial effect in coronary heart disease, hypertension, and inflammatory disorders [E. Mantzioris et al. (1995) Differences exist in the relationships between dietary linoleic and alpha-linolenic acids and their respective long-chain metabolites. Am. J. Clin. Nutr. 61(2): 320-324]. Yet, little is known about the hypotensive effect of the lignan components of flaxseed. Moreover, use of whole flaxmeal or oil components of flaxseed has been found to result in progressive weight gain due to the high caloric value of the oil components.
Flaxseed is known to contain a myriad of molecules including lignan and oil fractions. Secoisolariciresinol diglucoside (SDG) is the principal lignan from flaxseed.
Although flaxseed has been used as an edible grain in different parts of the world since ancient times, use of flaxseed was limited due to the presence of cyanogenic glucosides and diglucosides in the seeds as they may release cyanide upon hydrolysis. Also, flaxseed has to be used in large quantity to be effective.
In Westcott and Muir U.S. Pat. No. 5,705,618, issued January, 1998, there is described a practical method of extracting and purifying SDG. By this technique, SDG can be obtained in a purity of greater than 95%.
The purpose of the present invention is to provide a method of using flaxseed for medical purposes without the aforementioned drawbacks of cyanogenic glycosides, and caloric loads. SDG compound is obtained from natural food product (flaxseed), and hence it is expected to have non or minimal side effect if any. It is also an inexpensive drug as compared to other conventional drugs used in the treatment of hypertension and ischemic heart disease.
In accordance with this invention, it has been found that by administering SDG from flaxseed in substantially pure form to a human or non-human animal, elevated blood pressure can be reduced and hypertension can be prevented. The SDG serves to lower blood pressure by dilation of blood vessels. Its vasodilator (hypotensive) effect appears to be mediated primarily through the inhibition of guanylate cyclase, partly through inhibition of angiotensin I converting enzyme and blockade of angiotensin II receptor, and through histamine.
SDG is also useful for the treatment of ischemic heart disease (coronary artery disease) where the SDG serves to dilate the coronary blood vessels to supply more blood to the heart muscle. This abolishes ischemia of the heart and hence abolishes or prevents chest pain and other signs and symptoms associated with an ischemic heart. Also, by reducing the afterload (aortic pressure) because of lowering blood pressure, SDG serves to decrease the myocardial oxygen consumption thereby reducing ischemia of the heart.
A further associated use of SDG is for treating intermittent claudication, which is a leg pain while walking due to narrowing of the blood vessels of a leg muscle. Decreased blood flow to the leg muscle initiates the pain. SDG by dilating blood vessels increases the blood supply to the leg muscle and relieves the leg pain.
A still further associated use of SDG is for the treatment of heart failure, where it serves to reduce the afterload to the heart by lowering blood pressure. Thus, the heart is able to work against low arterial pressure thereby increasing the cardiac output.
Diabetic patients are known to suffer hypertension and SDG is effective in lowering the blood pressure of hypertensive patients with diabetes.
Unlike the uses of SDG described in U.S. Pat. No. 5,846,944, in the uses according to the present invention the SDG acts primarily to dilate blood vessels. This is achieved without the undesirable side effects of cyanogenic glycosides and caloric loads.
The SDG is preferably used at a high degree of purity of over 90%, with a purity of over 95% being the preferred. It can be administered orally, intraperitoneally or intravenously. It has been found to be highly effective in normotensives when given intravenously in the doses of 10-30 mg/kg body weight and in hypertensives when given intravenously in the doses of 1-15 mg/kg body weight, intraperitoneally in the doses of 5-200 mg/kg body weight, and orally in the dose of 100 mg/kg body weight. The oral doses may conveniently be in the form of tablets or capsules and the SDG may be used together with a variety of pharmaceutically cceptable diluents or carriers.